A multi-institution Group has been assembled to cooperate on the development of new drugs for the treatment and prophylaxis of HTLV-III infections. An integrated approach to rational drug design of anti-viral drugs has been developed by the Group. A broad screening program of testing of well characterized synthetic compounds and natural products using a variety of biochemical, in vitro, cell culture, and animal model systems is proposed. The rational approach to drug design demands detailed information regarding the active sites of specific virus proteins relevant to drug design. Experiments designed to yield additional information regarding the viral protease, reverse transcriptase, integrase, trans-activator and envelope gene are proposed. Animal tests are proposed using mouse and monkey models. Where possible mice will be used. However, the special features of the HTLV-III require that some compounds be tested using the Simian T-Lymphotropic virus type III (STLV-III) as this virus closely resembles HTLV-III in structure and pathology in rhesus monkeys. Experiments to develop the comparative molecular biology of STLV-III and HTLV-III relevant to purposes of drug development are proposed. The Group includes three laboratories from the Dana-Farber Cancer Institute (site of the Central Operations Office), the Smith, Kline and Beckman Research Laboratories, The Southwest Foundation for Medical Research, and a laboratory at the Columbia College of Physicians and Surgeons. Together these institutions provide a pool of research skills unattainable at any single institution. Areas of expertise represented include: chemical synthesis and natural product chemistry; protein chemistry, protein purification and protein X-ray crystallography; drug screening; molecular biology and molecular genetics; animal virology and in depth experience with retroviruses including HTLV-III, STLV-III, HTLV-I, II, murine, feline, avian and sheep retroviruses specifically; primate virology; veterinary medicine; clinical medicine and oncology; toxicology and pharmacology. The Smith, Kline and Beckman group is experienced in bringing components from the development stage to clinical trial.